Published on Thu Nov 16 2017

Direct injection of protamine-protected mRNA: results of a phase 1/2 vaccination trial in metastatic melanoma patients.

Benjamin Weide, Steve Pascolo, Birgit Scheel, Evelyna Derhovanessian, Annette Pflugfelder, Thomas K Eigentler, Graham Pawelec, Ingmar Hoerr, Hans-Georg Rammensee, Claus Garbe

In mice, injection of messenger RNA (mRNA) coding for tumor-associated antigens can induce antitumor immune responses. We injected intradermally protamine-stabilized mRNAs in 21 metastatic melanoma patients. No adverse events more than grade II have been observed.

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Abstract

In mice, injection of messenger RNA (mRNA) coding for tumor-associated antigens can induce antitumor immune responses and therefore offers a broadly applicable immunotherapy approach. We injected intradermally protamine-stabilized mRNAs coding for Melan-A, Tyrosinase, gp100, Mage-A1, Mage-A3, and Survivin in 21 metastatic melanoma patients. In 10 patients keyhole limpet hemocyanin (KLH) was added to the vaccine. Granulocyte macrophage colony-stimulating factor was applied as an adjuvant. Endpoints were toxicity and immune responses. No adverse events more than grade II have been observed. During treatment the frequency of Foxp3+/CD4+ regulatory T cells was significantly decreased upon mRNA vaccination in peripheral blood of the patients in the KLH arm, whereas myeloid suppressor cells (CD11b+HLA-DR lo monocytes) were reduced in the patients not receiving KLH. A reproducible increase of vaccine-directed T cells was observed in 2 of 4 immunologically evaluable patients. One of 7 patients with measurable disease showed a complete response. In conclusion, we show here that direct injection of protamine-protected mRNA is feasible and safe. The significant influence of the treatment on the frequency of immunosuppressive cells, the increase of vaccine-directed T cells upon treatment in a subset of patients together with the demonstration of a complete clinical response encourage further clinical investigation of the protamine-mRNA vaccine.